Hypoxia induces a physiologic endoplasmic reticulum (ER) stress in solid tumors. Previous studies have indicated that hypoxia is a major determinant of local, regional, and distant recurrence after anticancer therapy. While many investigators have pursued studies characterizing the hypoxia induced factor (HEF-1 and HIF-2) mediated response to hypoxia, we will investigate the role the unfolded protein response (UPR), a HIF-independent signaling pathway, on tumor growth. The UPR is an evolutionarily conserved pathway that functions to reduce protein accumulation in the ER resulting in an increased capacity to tolerate ER stress. We hypothesize that since the UPR is activated during hypoxia, it may be a critical regulator of cell survival during hypoxia and is necessary for tumor growth. In this proposal, we will analyze the effect of modulating XBP1 expression on tumor growth, determine the effect of hypoxia on ER associated degradation (ERAD), and investigate the role of an XBP1 target gene, EDEM (ER degradation enhancing alpha-manosidase-like protein) on tumor growth. Ultimately, these studies may not only lead to the development of novel anticancer therapies based upon inhibition of XBP1 in tumors, but may also provide fundamental insights into our understanding of tumorigenesis.